About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

December 21, 2011

AstraZeneca's Problems

Posted by Derek

Not exactly a load of happy holiday news from AstraZeneca here - they're already facing one of the nastiest patent cliffs in the industry (second only, and arguably, to Eli Lilly), and now they've had still more development compounds crash out on them.

There's olaparib (AZN-), which is an inhibitor of the DNA repair pathway enzyme PARP, Poly-ADP ribose polymerase. There are a number of PARP inhibitors making their way through the clinic, but olaparib's performance can't be giving comfort to anyone else in the field. It looked promising a couple of years ago in an ovarian cancer trial, but that, folks, was only progression-free survival. As time went on, it became clear that there wasn't going to be any benefit in overall survival, and that's what the world cares about, as it should. The compound's still in trials against other forms of cancer, and who knows, it might have better effects there. Oncology is a crap shoot if ever there was one. But ovarian cancer was the big first hope for AZ, and that's been written off.

The other compound that's hit the skids recently was TC-5214, mecamylamine, a nicotinic antagonist, which would have been a new mechanism for depression. But not if it doesn't work, and the compound missed its primary endpoint in the clinic, as I wrote about here last month. That one came in from Targacept, as olaparib came in from KuDOS, and these results have people wondering in the press about what this says about AstraZeneca's whole inlicensing strategy.

The problem is, these are two fields (cancer and depression) that have very high failure rates no matter who's doing the inlicensing. And while it's true that AZ seems to have had a lot of bad luck, some of that might just be the normal course of events if you're targeting these conditions. Having it happen while your other patents are expiring is bad, of course, but being in a position to have to depend on these therapeutic areas is a tough place to be to start with. (Not that there are a lot of safe places to work, true, but these are especially tricky). And it leads to things like this:

“AstraZeneca seems to have had more than its fair share of misfortune when it comes to the development pipeline,” analysts at Barclays Capital in London wrote in a note to investors today. “Additional development failures increase the probability that management will reassess the likely return on investment from additional R&D investment and cut costs further.”

Translation: Since AZ can't make money from its external purchases, they should/will cut internal research so that they have to depend on their external purchasing procedures even more...

Did that line of reasoning actually make sense to someone? Were they checked for brain function afterwards?

There's also the more general problem of knowing whether AZ made bad choices or whether they made good choices that turned out badly, and whether the purchasing choices they made were better than the research they would have generated internally for the same money. The inability to figure out the productivity of research is problematic here.

Derek: Is it not true that PARP inhibitors are selective only for triple negative cancer cells? My understanding from that initial Harvard study (synthetically lethal concept) was that the PARP inhibitors get better response from triple negative breast cancer cells (inherited defective gene). Given that why should it work for ovarian cancer? Correct me, if I am wrong. That said, how big is the PARP market?

Worth pointing out that they didn't just buy the Kudos compound, they bought the whole company with the intention of running it as a separate subsidiary. But AZ decided that they knew best, took all the compounds and fired everybody at Kudos. Who might have been in a better position to make judgements on what compound to progress. But AZ are genuinely screwed now. The 15billion purchase of Medimmune looks worse and worse. Some great scientists at AZ. Dire management.

Iniparib (another PARP inhibitor, Sanofi) was tested in triple negative breast cancer patients but failed.. incidently it is a very simple off the shelf molecule.

The synthetic lethal aspect involves the BRCA mutation, a subset of breast/ovarian cancer patients have this mutation and it was believed the additional treatment with a PARP inhibitor would push the tumor over the edge in terms of the DNA repair mechanism.. obviously it hasn't worked out that way which is a shame because some good science has gone into it... or maybe they are just using the wrong compounds and need to find some more potency? remains to be seen.

Actually, Sanofi did not test iniparib in BRCA mutants, which may well have contributed to the trial failure, given the PARPi hypothesis.

Indications are that in BRCA mutants, PARPi could still be a good strategy--but it seems now that multiple companies have chased the broader indication (and failed) rather than targeting the niche population likely to benefit from this treatment strategy.

Studies are not yet completed /published on the utility of PARP inhibitors in women with breast cancer (or ovarian cancer) where there is a genome BCRA1 or BCRA2 mutation. Perhaps in this setting, the PARP inhibitors will show their worth. And, there are PARP inibitor candidate that are more effective in vitro than the Sanofi drug. I'm not sure about the AZ drug.

In theory, PARP inhibitors could help in other cancers as well, since inhibition of DNA repair should make a cancer cell more susceptable to dna damaging chemotherapy. But it looks like in the settings recently committed to trial have not shown sufficient improvement, and hence the announcement. Let's hope that some progress can be made for this class of drugs. It is very disappointing when science finds another target for anti-cancer drug development and nothing comes of it. The anti-p170 glycoprotein MDR pump inhibitors were a big disappointment 15 years ago... studied extensively and nothing came of them.

Much as I like to blame management for all our woes I don't think we can in this case. These compounds looked promising and turned out not to live upto expectations-them's the breaks and that's why you do trials. Hopefully there'll be better news for pharma and for patients in future.

The Wall Street Journal (12/21, Inagaki, FitzGerald, Subscription Publication) reports that Japanese drugmaker Daiichi Sankyo Co. cut its profit forecast nearly in half and announced executive pay cuts, as it set aside $500 million to resolve a dispute between the FDA and its Ranbaxy subsidiary. The settlement, if approved by a federal court in Maryland, will resolve a ban the FDA placed in 2008 on imports of drugs made at two plants in India due to alleged violations of good-manufacturing rules and other infractions.

Here in the states you could never do that. Your best people in management (and please there are good and bad ones as in any field) would bolt immediately for your competitors. In Japan that doesn't happen nearly as much as people tend to stay at their companies forever.

It's a cultural difference in terms of the relationship between employer and employee and the expectations from each side.